The long term objective of this project is to define the fundamental mechanism of the major autoimmune disease, Systemic Lupus Erythematosus (SLE). Analysis of the structure and antigenic specificities of the receptors expressed by the select T helper (TH) cells that induce the production of pathogenic autoantibodies in SLE, may lead to an understanding of the etiologic mechanism of lupus in humans. The goal of the first set of specific aims is to define the antigen receptor mediated signal for the pathogenic autoantibody-inducing Th cells of human lupus. Critical peptide autoepitopes in nucleosomal antigens that trigger lupus Th cells will be identified by eluting naturally processed peptides from MHC molecules and by overlapping peptide synthesis. The disease relevance of the peptide epitopes will be determined in vivo using a SCID-human lupus adoptive transfer system. After fine mapping of MHC and TCR contact residues in the peptide autoepitopes, altered peptide ligands will be designed for blocking pathogenic autoantibody-inducing Th cells from lupus patients. The objective of the second set of specific aims is to define the role of costimulatory signals in the cognate interaction between the select Th and B-cells of lupus that leads to the production of pathogenic autoantibodies. The role of the CD40 ligand molecule (CD40L) in providing the second signal via CD40 on lupus B-cells for production of pathogenic autoantibodies will be studied. The mechanism of hyperexpression of CD40L in the T-cells, and more unexpectedly in the B-cells of lupus patients, will be investigated. Proposed studies on the regulation of CD40L gene expression may reveal an intrinsic defect in lupus which will be important in understanding the basic mechanism of T-cell and B-cell hyperactivity in this disease and will be of diagnostic and prognostic value as well.